17-45440366-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014798.3(PLEKHM1):c.2838-140G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 816,832 control chromosomes in the GnomAD database, including 787 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.032 (113 hom., cov: 33)
  • Exomes 𝑓: 0.038 (674 hom.)
• Consequence: PLEKHM1 NM_014798.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.32

Genes affected

PLEKHM1 (HGNC:29017): (pleckstrin homology and RUN domain containing M1) The protein encoded by this gene is essential for bone resorption, and may play a critical role in vesicular transport in the osteoclast. Mutations in this gene are associated with autosomal recessive osteopetrosis type 6 (OPTB6). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-45440366-C-T is Benign according to our data. Variant chr17-45440366-C-T is described in ClinVar as [Benign]. Clinvar id is 1253364.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.051 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHM1	NM_014798.3	c.2838-140G>A		intron_variant		ENST00000430334.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHM1	ENST00000430334.8	c.2838-140G>A		intron_variant		1	NM_014798.3	P1

Frequencies

GnomAD3 genomes AF: 0.0318 AC: 4847 AN: 152242 Hom.: 113 Cov.: 33

Gnomad AFR AF: 0.00957

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0193

Gnomad ASJ AF: 0.0501

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00558

Gnomad FIN AF: 0.0284

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0525

Gnomad OTH AF: 0.0315

GnomAD4 exome AF: 0.0384 AC: 25526 AN: 664472 Hom.: 674 Cov.: 8 AF XY: 0.0364 AC XY: 12827 AN XY: 352794

Gnomad4 AFR exome AF: 0.0104

Gnomad4 AMR exome AF: 0.0155

Gnomad4 ASJ exome AF: 0.0420

Gnomad4 EAS exome AF: 0.0000595

Gnomad4 SAS exome AF: 0.00478

Gnomad4 FIN exome AF: 0.0342

Gnomad4 NFE exome AF: 0.0508

Gnomad4 OTH exome AF: 0.0362

GnomAD4 genome AF: 0.0318 AC: 4845 AN: 152360 Hom.: 113 Cov.: 33 AF XY: 0.0293 AC XY: 2181 AN XY: 74502

Gnomad4 AFR AF: 0.00955

Gnomad4 AMR AF: 0.0193

Gnomad4 ASJ AF: 0.0501

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.0284

Gnomad4 NFE AF: 0.0525

Gnomad4 OTH AF: 0.0312

Alfa AF: 0.0191 Hom.: 9

Bravo AF: 0.0309

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.58
Dann	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs117755594; hg19: chr17-43517732;